We began a new line of inquiry into the role of neurotrophic factors in mediating some of the long-term phenotypic, structural and deleterious effects of stress in the brain. The goal of this project is to determine if neurotrophic factors might be important for establishing long-term changes in stress sensitivity. Because nerve growth factors are necessary for normal development and maintenance of neurons while their absence may lead to neuronal degeneration, we considered the possibility that stress might affect expression of nerve growth factors in the brain. We found that immobilization stress, acute or chronic, reduced brain- derived neurotrophic factor (BNDF) mRNA levels in the hippocampus and throughout the limbic system in rats. In contrast, a related growth factor neurotrophin-3 (NT-3) increased in the hippocampus and the locus coeruleus, but only in response to repeated stress. Antidepressant drugs and electroconvulsive or kindled seizures also affected neurotrophic factor expression in the brain but in an opposite fashion to that produced by stress. These findings raise the possibility that neurotrophic factors may be important in the pathophysiology of stress as well as in the mechanism of action of antidepressant treatments.